Diabetes mellitus is one of the most typical metabolic diseases from which 200 million people are currently suffering in the world. The number of diabetic patients is predicted to exceed 300 million people in the year 2025, and is considered to be particularly increased in the South-East n region and the Western Pacific region where the entire populations are increasing. Also, in Japan, currently the diabetic population including patients on the borderline is considered to exceed 15 million people, and there is concern of further increase in the future.
Diabetes mellitus is largely classified into two types. Insulin-dependent diabetes mellitus (IDDM), referred to as type 1, is a disease in which pancreatic β cells are progressively destroyed by the immune system to cause a loss of insulin-producing cells, and this constitutes 5 to 10% of the entire diabetic population. Non-insulin-dependent diabetes mellitus (NIDDM), referred to as type 2, occurs as a result of defective responsiveness of tissues to insulin (insulin resistance) in the intake of glucose under the presence of a normal to high level of insulin, which also leads to the exhaustion of β cells. At present, type 2 diabetic patients constitutes 90 to 95% of the entire diabetic patients.
Currently, treatments such as insulin are performed against the dysfunction of β cells in the type 1 and the advanced-stage type 2 diabetes. However, there are problems in that the postprandial blood glucose level does not return to normal depending on the symptom, and the like. Moreover, the concerned treatments must be performed while avoiding hyperglycemia, hypoglycemia, metabolic acidosis, and ketosis, and need to be carefully programmed.
Furthermore, with respect to type 2 diabetes, treatments using drugs which promote the insulin production or secretion from the β cells, or drugs which improve the insulin resistance, are generally performed. However, these drugs promote the insulin production or secretion irrespective of the blood glucose level, and thus the blood glucose level should be controlled by diet so as not to fall into a hypoglycemic state or the like. There are also drawbacks of having side effects such as abdominal bloating, meteorism, increased flatulence, loose stools, diarrhea, and abdominal pain. Moreover, in cases of the insulin resistance improvers, it is reported that, as a result of the examination of their effects by hemoglobin Alc (HAlc) values or the like, the symptoms are not satisfactorily improved (Non-patent Document 1), and that side effects such as heart failure may possibly be induced by long term usage.
On the other hand, glucagon-like peptide-1 (GLP-1), a hormone secreted from L cells which are scattered in the gastrointestinal tract, is confirmed to have effects such as promoting a strong insulin secretion, stimulating the satiety center, and suppressing the gastrointestinal peristalsis, stimulated by food (Non-patent Document 2). These effects are all considered to be associated with inhibitory effects on rapid increase in the blood glucose level caused by food intake.
The effects of this GLP-1 stop working when the blood glucose level drops to 60 mg/dL or less, and thus it can be said that therapies using GLP-1 are more readily capable of controlling the blood glucose level as compared to conventional insulin therapies or the like (Non-patent Document 3). Further, GLP-1 has important functions such as an ability to promote the differentiation and proliferation of β cells to protect the pancreas, an ability to inhibit gluconeogenesis in the liver, an ability to improve the insulin resistance in cells, or an ability to improve peripheral glucose disposal (Non-patent Documents 4 and 5).
Therefore, many pharmaceutical manufacturers are dedicated to research with the expectation of a therapeutic effect of GLP-1 on type 2 diabetes. However, GLP-1 is extremely unstable in vivo, and thus it is required for example to optimize the administration method and the administration route, and to search for functional analogues which are highly stable in vivo. Practical implementation is still on the way at the present stage.
Therefore, research is being conducted not only on the direct administration of GLP-1 but also on the substances which promote the GLP-1 release in vivo, and naturally-derived components which have a GLP-1 release promoting effect are known.
For example, Patent Document 1 discloses that acid caseins and the like have a promoting effect on GLP-1 secretion. FIG. 1 of the Patent Document 1 shows results of the examination on the promoting effect on GLP-1 secretion by an in vitro test method. According to these, the promoting effect on GLP-1 secretion of acid caseins is approximately twice as compared to the control. Moreover, the promoting effect on GLP-1 secretion of acid-soluble proteins of casein micelles is approximately six times as compared to the control.
Moreover, Patent Document 2 discloses that a casein glycomacropeptide (CGMP) has a promoting effect on GLP-1 secretion. CGMP is a peptide obtained by cleaving the bond between phenylalanine 105 and methionine 106 of κ-casein with chymosin. FIG. 1 and FIG. 2 of Patent Document 2 show results of the examination on the promoting effect on GLP-1 secretion by an in vitro test method. According to them, the promoting effects on GLP-1 secretion of CGMP calcium salt and CGMP sodium salt are approximately twice to three times as compared to the control.
Since these components are naturally-derived and highly safe, it is expected that the administration thereof into diabetic patients including patients on the borderline can lead to the control of the postprandial blood glucose level without causing hypoglycemia.
(Patent Document 1) European Patent Application, Publication No. 1367065
(Patent Document 2) PCT International Publication No. WO 01/37850 Pamphlet
(Non-patent Document 1) Ghazzi et al., Diabetes, Vol. 46, No. 3, p. 433-439 (1997)
(Non-patent Document 2) Wettergren A, et al., Digestive Diseases and Sciences (Dig Dis Sci), Vol. 38, p. 665-673 (1993)
(Non-patent Document 3) Nauck et al., Diabetologia, Vol. 36, p. 741-744 (1993)
(Non-patent Document 4) M. L. Vellanueva et al., Diabetologia, Vol. 37, p. 1163 (1994)
(Non-patent Document 5) D. J. Drucker, Diabetes, Vol. 47, p. 159 (1998)